Experienced Thrombocytopenia Research Articles

Low-Dose Valganciclovir Prophylaxis Against Cytomegalovirus in Intermediate-Risk Liver and Dual-Abdominal Transplant Recipients.

Low-dose valganciclovir (VGC) for cytomegalovirus (CMV) prophylaxis post-transplant has been employed due to cost and safety. The incidence of CMV disease in CMV intermediate-risk liver recipients at 1-year after standard-dose prophylaxis is approximately 5%. However, there are limited data on outcomes after using a "true" low-dose VGC prophylaxis regimen in liver and dual-abdominal transplant recipients as VGC was not dose-adjusted in all patients with impaired renal function in prior studies. The objective was to assess the incidence of CMV associated with low-dose VGC prophylaxis in CMV intermediate-risk liver, simultaneous pancreas-kidney (SPK), and simultaneous liver-kidney (SLK) recipients with creatinine clearance (CrCl) >60 mL/min. This was a retrospective review of CMV intermediate-risk liver, SPK, and SLK recipients with CrCl >60 mL/min transplanted January 2018 to June 2022 who received VGC 450 mg daily for prophylaxis. The primary outcome was incidence of CMV infection 6-months post-transplant. Ninety-nine transplant recipients were included (79 liver, 11 SPK, 9 SLK). The primary outcome occurred in 13% of patients (liver 10%, SPK 36%, SLK 10%), including 1 case of CMV disease and 3 breakthrough infections. In addition, 6 patients experienced CMV infection between 6-months and 1-year. Recurrence occurred in 3 patients. There was no evidence of CMV resistance. Thirty patients experienced neutropenia within 1-year, 32 were prescribed granulocyte-colony stimulating factors, and 5 experienced thrombocytopenia. Two patients died due to graft-vs-host disease. Low-dose VGC prophylaxis led to comparable CMV infection rates at 6-months in CMV intermediate-risk liver and SLK recipients. However, as SPK recipients displayed higher rates of CMV infection, low-dose VGC should be avoided in this population.

Clinical Outcomes of Trimethoprim/Sulfamethoxazole in Critically Ill Patients with Stenotrophomonas maltophilia Bacteremia and Pneumonia Utilizing Renal Replacement Therapies.

Background: The clinical outcomes of usual doses of Trimethoprim-sulfamethoxazole (TMP/SMZ) for treating S. maltophilia in critically ill patients on renal replacement therapies (RRT) have not been established. We sought to assess the clinical outcomes of TMP/SMZ in patients with sepsis utilizing RRT. Methods: A retrospective study was performed on all critically ill adult patients with S. maltophilia infections who received RRT between May 2015 and January 2022. The primary endpoint was clinical cure while the secondary endpoints were microbiologic cure, 30-day infection recurrence, and mortality. Results: Forty-five subjects met the inclusion criteria. The median age was 70.0 [interquartile range (IQR): 63.5-77] years, 57.8% were males, and the median body mass index was 25.7 [IQR: 22-30.2] kg/m2. Clinical success and failure were reported in 18 (40%) and 27 (60%) cases, respectively. There was no significant difference between the 30-day reinfection rates of both groups; however, mortality was significantly higher in the clinical failure group, involving 12 patients (44.4%), versus none in the clinical success group (p = 0.001). The median daily dose of TMP/SMZ upon continuous veno-venous hemofiltration was 1064 [IQR: 776-1380] mg in the clinical cure group vs. 768 [IQR:540-1200] mg in the clinical failure group (p = 0.035). Meanwhile, the median dose for those who received intermittent hemodialysis was 500 [IQR: 320-928] mg in the clinical success group compared to 640 [IQR: 360-1005] mg in the clinical failure group (p = 0.372). A total of 55% experienced thrombocytopenia, 42% hyperkalemia, and 2.2% neutropenia. The multivariable logistic regression analysis showed that the total daily dose at therapy initiation was the only independent factor associated with clinical success after adjusting for different variables including the body mass index [Odds ratio 1.004; 95% confidence interval: (1-1.007), p = 0.044]. Conclusions: Although the S. maltophilia isolates were reported as susceptible, TMP/SMZ with conventional doses to treat bacteremia and pneumonia in critically ill patients utilizing RRT was associated with high rates of clinical and microbiologic failure as well as with mortality. Larger outcomes and pharmacokinetics studies are needed to confirm our findings.

Safety and efficacy of eltrombopag in patients with post-CAR T cytopenias.

While chimeric antigen receptor (CAR) T-cell therapy has revolutionized the treatment outcomes of relapsed/refractory hematological malignancies, this therapy is associated with post-treatment cytopenias, which can pose a challenge to its safe administration. This study describes the management of post-CAR T cytopenias using the thrombopoietin mimetic eltrombopag. This retrospective analysis included adult patients with lymphoma or myeloma who received CAR T-cell therapy at two academic medical centers. Eltrombopag was initiated for patients who had persistent high-grade leukopenia and/or thrombocytopenia beyond 21 days post-CAR T infusion. Risk factors and outcomes were assessed and compared for patients who did or did not receive eltrombopag. Among the 185 patients analyzed, a majority (88%) experienced thrombocytopenia or leukopenia at day +30 post-CAR T infusion. A total of 42 patients met the criteria for eltrombopag treatment and initiated therapy. Patients who received eltrombopag were more likely to have pre-existing cytopenias at lymphodepletion, receive bridging therapy, experience an infection, or require intensive care. Recovery from cytopenias occurred within 180 days for a majority (94%) of patients. The use of eltrombopag for post-CAR T leukopenia and thrombocytopenia was considered safe without any significant toxicities. The use of eltrombopag for post-CAR T cytopenias might be effective in a high-risk patient population but requires further study.

Use of Eltrombopag for Post-CAR T Cytopenias: A Multi-Institutional Experience

Background: Cytopenias following chimeric antigen receptor T (CAR T) cell therapy are common and can be profound and/or prolonged, leading to increased morbidity and mortality. Supportive care is the mainstay of management but strategies to reduce the duration and severity of cytopenias have yet to be optimized. One such strategy extrapolated from experience in aplastic anemia is the use of thrombopoietin (TPO) receptor agonists, like eltrombopag. Eltrombopag has been used off-label for several years for this indication, however, limited data exists regarding the safety and efficacy of its use after CAR T-cell therapy. Methods: Patients ≥ 18 years of age treated with CAR T-cell therapy for either lymphoma or myeloma at two academic medical centers between January 2018 and January 2023 were included in a retrospective analysis. Use of eltrombopag was initiated at the KUMC for patients who had received CAR T and subsequently had persistent cytopenias at day +30 as evidenced by at least one of four criteria: grade 3 or 4 leukopenia, grade 4 thrombocytopenia, growth factor dependency, or platelet transfusion dependency. Use of eltrombopag was initiated at the MUSC for patients who had received CAR T and had grade 4 thrombocytopenia at day +21 and beyond post-CAR T infusion. Baseline patient and disease characteristics as well as variables describing safety and efficacy of eltrombopag for the treatment of persistent high-grade leukopenia and/or thrombocytopenia beyond day +21 post CAR T infusion were collected and summarized using descriptive statistics. Results: A total of 185 patients were included in this analysis. Of these, 163 (88%) experienced thrombocytopenia or leukopenia at day +30 post-CAR T infusion. A total of 42 patients met institutional criteria for eltrombopag treatment and initiated therapy. Median time to initiation of eltrombopag was 33 days (range 28-50) from infusion, with no significant differences between the two institutions (30 days at KUMC vs 36 days at MUSC, p=0.19). Median duration for the use of eltrombopag was 63 days (range 32-172) and KUMC used eltrombopag for a longer duration than MUSC (108 days vs 32 days, p=0.03). There were no statistically significant differences in bleeding events in the eltrombopag vs non-eltrombopag groups, p=0.053, and no reported cases of deep vein thrombosis or pulmonary embolism (DVT/PE) after initiating eltrombopag. Patients on eltrombopag were more likely to have infections (24 (57%) vs 42 (35%), p<0.01) and admission to intensive care unit (16 (38%) vs 20 (17%), p<0.01) when compared to the non-eltrombopag group. At day +30, 74 (45%) patients in the entire study population had grade 3 or higher leukopenia or thrombocytopenia, with 39 (93%) and 25 (29%) patients in the eltrombopag and non-eltrombopag groups with grade 3 or higher cytopenias, respectively ( p<0.001). By day +90, only 18 (35%) patients in the evaluable population had grade 3 or higher leukopenia or thrombocytopenia, with 12 (50%) and 6 (22%) patients in the eltrombopag and non-eltrombopag groups with grade 3 or higher cytopenias, respectively ( p=0.046). By day +180, all but ten patients in the evaluable population had not recovered to less than a grade 3 cytopenia with no significant difference in cytopenias between the two groups. With a median follow up of 12 months (range 1-34) for the entire patient population, median PFS was lower for the eltrombopag group (13 months) compared to the non-eltrombopag group (16 months, p=0.02). When stratified by disease, this association was observed only for the lymphoma patients, with a median PFS of 8.5 months in the eltrombopag group compared to a median PFS of 17 months in the non-eltrombopag group, p=0.01 (Table 1). Similarly, for the entire patient population, median OS was lower for the eltrombopag group (14 months) compared to the non-eltrombopag group (18 months, p=0.01). When stratified by disease, this association was observed only for the lymphoma patients, with a median OS of 14 months in the eltrombopag group compared to 18 months in the non-eltrombopag group ( p<0.01). Conclusions: In this first of its kind real-world experience, use of eltrombopag for post-CAR T leukopenia and thrombocytopenia was considered effective in recovery of counts and prevention of bleeding in a high-risk patient population. The use of eltrombopag for post-CAR T cytopenias was considered safe without any significant toxicities of thrombosis or myelodysplasia.

Analisis Jumlah Trombosit Dan Leukosit Pada Pasien Dengue Hemorrhagic Fever (DHF) Di Rumah Sakit Umum Daerah Kabupaten Barru

Dengue hemorrhagic fever (DHF) is a chronic fever disease caused by infection with the dengue virus which is transmitted through the bite of the Aedes aegypti and Aedes albopictus mosquitoes. Laboratory abnormalities that are often found in DHF patients are thrombocytopenia and leukopenia. This study aims to determine the results of examination of platelet and leukocyte counts in dengue hemorrhagic fever (DHF) patients. This study used a descriptive design with the population being all dengue hemorrhagic fever (DHF) patients at the Barru District General Hospital. The sample consisted of 30 DHF patients whose platelet and leukocyte counts were checked using a hematology analyzer for 3 consecutive days of hospitalization. The sampling technique in this research is the purposive sampling method. The results of the study showed that there were 30 DHF patients consisting of 14 (47%) men and 16 (53%) women with the highest age found `DHF being 8 - 12 years old, 10 people (33.33%). On the first day of hospitalization, 29 people experienced thrombocytopenia and 1 person had normal platelets. On the second day of hospitalization, 25 people experienced thrombocytopenia and 5 people had normal platelets. On the third day of hospitalization, 11 people experienced thrombocytopenia and 19 people had normal platelets. On the first day of hospitalization, 17 people experienced leukopenia, 11 people had normal leukocytes and 2 people had leukocytosis. On the second day of hospitalization, 8 people experienced leukopenia and 22 people had normal leukocytes. On the third day of hospitalization, 3 people experienced leukopenia and 27 people had normal leukocytes. This study shows that the majority of DHF patients experience thrombocytopenia while the platelet count tends to be normal.

A Combined Phase 0/2 "Trigger" Trial of Niraparib in Combination with Radiation in Patients with Newly-Diagnosed Glioblastoma

Poly ADP-ribose (PAR) polymerase (PARP) mediates DNA damage response. Niraparib is an investigational PARP1/2-selective inhibitor. We conducted a combined phase 0/2 study to evaluate niraparib pharmacokinetics (PK) and pharmacodynamics (PD) in patients with newly-diagnosed glioblastoma (GBM), graduating patients to a phase 2 study evaluating a therapeutic regimen of niraparib with concurrent conventionally-fractionated radiotherapy (RT) in O6-methylguanine methyltransferase (MGMT) unmethylated tumors exceeding a prespecified PK threshold in non-enhancing tumor. Patients with presumed newly-diagnosed GBM were enrolled in a phase 0 study receiving 4 days of niraparib (300 or 200 mg QD) prior to planned resection 3-5 or 8-12 hours following the last dose. Tumor tissue (enhancing and non-enhancing regions), cerebrospinal fluid (CSF), and plasma were collected. Total and unbound niraparib concentrations were measured using validated LC-MS/MS methods. PARP inhibition was assessed by quantification of PAR induction after 10 Gy ex vivo irradiation in surgical tissue compared to non-irradiated control tissue. A PK 'trigger' determined eligibility for the therapeutic phase 2 expansion portion of the study. This was defined as unbound [niraparib] > 5-fold biochemical IC50 (i.e., 19 nM) in non-enhancing tumor. Patients with MGMT unmethylated tumors exceeding this PK threshold were eligible for expansion phase dosing of niraparib with concurrent RT followed by a maintenance phase of niraparib. Patients with MGMT methylated tumors were not eligible for the expansion phase and proceeded with temozolomide (TMZ) plus RT followed by maintenance TMZ. RT dose was 60 Gy in 30 fractions using volumetric-modulated arc therapy (VMAT). All 29 patients enrolled in the phase 0 portion of the study met the PK threshold. In non-enhancing regions, the mean unbound concentration of niraparib was 258.2 nM. The suppression of PAR levels after ex vivo RT was observed in 79% of the patients (17/22). Sixteen patients had unmethylated tumors, and of those, 11 patients enrolled in phase 2. Five of the 6 initial patients enrolled in phase 2 experienced thrombocytopenia related to niraparib, and 3/5 cases were deemed serious and life-threatening. Consequently, starting dose in both phases was lowered to 200 mg, and no serious AEs were observed thereafter. At a median follow-up of 8.1 months [range: 6.0-12.9 months], 6-month PFS was 64% with 4 patients remaining on treatment and 5 patients ongoing survival follow-up. Niraparib achieves pharmacologically-relevant concentrations in non-enhancing, newly-diagnosed GBM tissue in excess of any other studied PARP inhibitor. When delivered with concurrent RT, niraparib was well-tolerated, with low rates of grade 3+ toxicity. Initial clinical efficacy data are encouraging.

Clinical Manifestations and Risk Factors of Tigecycline-Associated Thrombocytopenia.

Thrombocytopenia, characterized by a diminished platelet count, emerged as the most frequently reported coagulation dysfunction event according to the FDA Adverse Event Reporting System (FAERS) database. In recent years, numerous clinical studies have investigated the potential link between tigecycline usage and the occurrence of hypofibrinogenemia. However, a research gap remains in comprehensively examining the association between tigecycline and thrombocytopenia in real-world settings. This study was conducted to explore the incidence and clinical manifestations of tigecycline-associated thrombocytopenia. A retrospective case-control study of patients treated with tigecycline was conducted between January 2018 and June 2022. In total, 373 patients were included in this study. Among these patients, 12.3% experienced thrombocytopenia. The onset of thrombocytopenia occurred within a range of 2 to 22 days after the initiation of tigecycline, with a median period (25-75th percentile) of 9 (6-11) days. Among the patients manifesting thrombocytopenia, 60.9% exhibited mild-to-moderate cases (grades 1-2) while 39.1% endured severe cases (grades 3-4). Multivariate analysis delineated several factors as independent risk factors for thrombocytopenia. Notably, advanced age (≥74 years) (p=0.028), risk of malnutrition (p<0.001), tigecycline therapy for ≥7 days (p=0.003), DBIL>8.1μmol/L (p<0.001)), BUN>8.1mmol/L (p=0.002) emerged as independent risk factors associated with thrombocytopenia. When comparing the control group to the thrombocytopenia group, 70.7% of patients in the control group exhibited 0-2 risk factors, while all patients in the thrombocytopenia group demonstrated risk factors. Specifically, 95.7% of patients in the thrombocytopenia group presented with three to five risk factors, with only 4.4% having 0-2 risk factors. Tigecycline administration is associated with thrombocytopenia. Healthcare professionals should exercise vigilance, particularly in cases of severe tigecycline-associated thrombocytopenia, and undertake routine monitoring of patients' platelet counts, especially for those who possess three or more risk factors.

Clinical Improvement with Therapeutic Plasma Exchange in Neuroimmunological Children: A Single Center Experience

Background: Neuroimmunological diseases in children encompass a range of disorders that lead to neurological complications in patients due to immune responses and systemic circulating antibodies. Limited research has been conducted on therapeutic plasma exchange’s efficacy and potential side effects in children with neuroimmunological diseases. Objectives: This study aimed to investigate this procedure’s effectiveness and potential side effects in children afflicted by these diseases. Methods: This cross-sectional study examined a cohort of 18 children with neuroimmunological diseases who were admitted to the neurology department of Mofid Hospital over one year from March 2021 and underwent therapeutic plasma exchange. Results: The study included 18 patients, with an equal distribution of 9 females and 9 males. A total of 121 procedures were performed across 6 different disease groups: Multiple Sclerosis (22%, n = 4), Autoimmune Encephalitis (22%, n = 4), Neuromyelitis Optica Spectrum Disorder (22%, n = 4), Guillain-Barré syndrome (22%, n = 4), Acute Disseminated Encephalomyelitis (6%, n = 1), and Optic Neuritis (6%, n = 1). Following the plasma exchange, 17 patients (95%) showed immediate clinical improvement, while one patient diagnosed with optic neuritis did not respond to the treatment. During the follow-up period, 14 patients (78%) demonstrated significant improvement, one patient (6%) showed moderate improvement, and two patients (11%) exhibited mild improvement compared to their pre-plasmapheresis condition. Laboratory examinations revealed that only one patient experienced thrombocytopenia, which resolved without requiring treatment. No complications were observed during the follow-up visits for any of the patients. Conclusions: Plasma exchange is a safe procedure for children with neuroimmunological diseases and yields favorable clinical responses.

A phase 0/2 trigger trial of niraparib in patients with newly diagnosed glioblastoma.

2069 Background: Poly (ADP-ribose) polymerase (PARP) mediates DNA damage response; niraparib is an investigational PARP1/2-selective inhibitor. This Phase 0 study evaluates newly-diagnosed glioblastoma (GBM) tumor pharmacokinetics (PK) and pharmacodynamics (PD), graduating patients with O6-methylguanine methyltransferase (MGMT) unmethylated tumors into a therapeutic regimen of niraparib plus fractionated radiotherapy when high unbound drug concentrations are present in gadolinium-nonenhancing tumor. Methods: Patients with presumed newly-diagnosed GBM were enrolled in a phase 0 study receiving 4 days of niraparib (300/200 mg QD) prior to planned resection 3-5 or 8-12 hours following the last dose. Tumor tissue (enhancing and non-enhancing regions), cerebrospinal fluid (CSF), and plasma were collected. Total and unbound niraparib concentrations were measured using validated LC-MS/MS methods. PARP inhibition was assessed by quantification of PAR induction after 10 Gy ex vivo irradiation in surgical tissue compared to non-irradiated control tissue. A PK ‘trigger’ determined eligibility for the therapeutic expansion phase and was defined as unbound [niraparib] &gt; 5-fold biochemical IC50 (i.e., 19 nM) in non-enhancing tumor. Patients with MGMT unmethylated tumors exceeding this PK threshold were eligible for expansion phase dosing of niraparib plus radiotherapy followed by a maintenance phase of niraparib. Results: All patients (n=35) enrolled in the phase 0 portion of the study met the PK threshold. In non-enhancing tumor regions, the mean unbound concentration of niraparib was 253.2 nM in 32 evaluable GBM patients. The suppression of PAR levels after ex vivo radiation was observed in 75% of the patients (18/24). Eleven out of 18 patients with unmethylated tumors enrolled in phase 2. Five of the 6 initial patients enrolled in phase 2 experienced thrombocytopenia related to niraparib, and 3/5 cases were deemed serious and life-threatening. Consequently, starting dose in both phases was lowered to 200 mg, and no serious AEs were observed thereafter. At a median follow-up of 8.1 months [range: 6.0-12.9 months], PFS6 was 64% (n=11) with 4 patients remaining on treatment and 5 patients ongoing survival follow-up. Conclusions: Niraparib achieves pharmacologically-relevant concentrations in non-enhancing, newly-diagnosed GBM tissue in excess of any other studied PARP inhibitor. Clinical trial information: NCT05076513 .

Prognostic significance of early platelet dynamics in Staphylococcus aureus bacteremia

BackgroundPlatelets are recognized as key immune effectors, but they are targets of bacterial virulence factors. In the present study, we aimed to examine the relationship between early platelet dynamics and the outcome of Staphylococcus aureus bacteremia (SAB).MethodElectronic medical records of adult patients hospitalized for SAB between July 2012 and November 2020 were retrospectively reviewed for relevant demographic, laboratory, and clinical data. The outcome endpoints were mortality and microbial persistence.ResultsAmong the 811 patients evaluated, 29% experienced thrombocytopenia on Day 1. Platelet count nadir occurred on Days 2–3 following SAB onset, and Day 4 was a determining point of platelet count trajectory and mortality. Mortality risk was 6% or less for those with normal platelet count by Day 4 regardless of whether they experienced thrombocytopenia on Day 1, but the risk increased to 16–21% for those who experienced thrombocytopenia on Day 4 regardless of whether they had normal platelet count on Day 1 or sustained thrombocytopenia. The duration of bacteremia was prolonged by one day (median 3 d vs. 2 d) for those with sustained thrombocytopenia compared to those without.ConclusionEarly platelet dynamics during SAB have prognostic significance and represent an early window for potential platelet-directed therapeutic interventions to improve outcome.

Drug-induced thrombocytopenia associated with trastuzumab in a patient with HER2-positive recurrent gastric cancer

Here, we report a 57-year-old female patient with HER2-positive recurrent gastric cancer who experienced drug-induced thrombocytopenia associated with trastuzumab, a humanized anti-HER2 monoclonal antibody. Shortly after the initiation of S-1, oxaliplatin, and trastuzumab chemotherapy, the patient experienced severe thrombocytopenia and did not respond to platelet transfusions. Based on the findings of increased numbers of polynuclear megakaryocytes in the bone marrow and an elevated level of platelet-associated IgG (PA-IgG), the patient was diagnosed with drug-induced thrombocytopenia (DITP). The platelet count recovered rapidly with oral prednisolone (1 mg/kg). Since we initially suspected oxaliplatin as the causal agent, S-1 was restarted as a monotherapy, followed by trastuzumab after a 3-week interval, without oxaliplatin. On the second day after the addition of trastuzumab, severe thrombocytopenia occurred again, which suggests that trastuzumab was responsible for the DITP. The patient no longer experienced severe thrombocytopenia during the subsequent S-1 and oxaliplatin chemotherapy, which supports this hypothesis.

Immunodeficiency Caused Byheterozygous RAG1 Gene Mutation in a Boy Manifested As Severe Granulomatous Diseases and Eosinophilia: A Case Report

Severe combined immunodeficiency (SCID) is an inherited diseases caused by the defective development of T- and/or B-lymphocytes refractory to common therapy. We report a 13-year old boy with combined immunodeficiency caused by a heterozygous mutation at cDNA position 1435 (c.1435C>T) in RAG1 gene. His father and grand-father carried the same heterozygous RAG1 gene mutation, and experienced anaphylactic rhinitis. His mother had mutations in 6 immunodeficiency-related heterozygous genes but no RAG1 mutation, and experienced thrombocytopenia. Both his parents had normal NK and T cell numbers, and serum immunoglobulin (Ig) levels. After birth, this patient had severe allergies to many food and drugs, and suffered from recurrent upper and lower respiratory tract infections every year. After admission, the patient complained of a generalized body rash with itches lasting about several years. We found severe granuloma lesions in the face, mouth and nose, lymphadenectasis and splenomegaly by physical examination (Figure 1a). Laboratory examinations demonstrated that he had a high eosinophilic granulocyte count as 2.19×109/L, but decreased NK cell numbers and CD4+/CD8+ T cell ratios, and IgG, IgM and IgA serum levels. This patient has been previously treated with immune-modulatory drugs including anti-histamine drugs, prednisone, γ-globulin, and chemotherapy including Cyclophosphamide, but lacking clinical improvement. In our center, after Methotrexate (1g/m2 q.w.)+L-asparaginase (10000 unit q.d.×10 days) + Dexamethasone (10mg/m2q.d.×5 days) chemotherapy, and immune enhancement therapy with γ-globulin(400mg/kg×5 days per month), the patient got his symptoms ameliorated (Figure 1b). Haploidentical hematopoietic stem cell transplantation (HCT) from his HLA 7/10 matched mother was subsequently applied, and the patient remained remission without HCT-related complications for at least 8 months after transplantation (Figure 1c). Our results thus showed the immune disorder in a boy caused by a novel heterozygous RAG1 gene c.1435C>T mutation which has been efficiently treated by our specific chemotherapy combined with HCT. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Gemcitabine, carboplatin and veliparib in multiple relapsed/refractory germ cell tumours: The GCT-SK-004 phase II trial

BackgroundPatients with multiple relapsed/refractory germ cell tumours (GCTs) have an extremely poor prognosis. PARP (poly-ADP-ribose polymerase) is overexpressed in GCTs compared to normal testes, and PARP overexpression is an early event in GCT development. This study aimed to determine the efficacy and toxicity of gemcitabine, carboplatin and the PARP inhibitor veliparib in patients with multiple relapsed/refractory GCTs. MethodsFifteen patients with multiple relapsed/refractory GCTs were enrolled in this phase II study from October 2016 to October 2020. Gemcitabine was administered at a dose of 800mg/m2 on days 1 and 8 every 3 weeks; carboplatin at a target AUC of 4 on day 1 every 3 weeks; and veliparib at a dose of 250mg b.i.d. throughout. The primary end point was 12-month progression-free survival (PFS). ResultsThe median number of treatment cycles was 4 (range 2-8). Twelve-month PFS was achieved in 1 (6.7 %) patient. The median PFS was 3.1 months (95 % CI 2.2-3.9), and the median overall survival was 10.5 months (95 % CI 8.9-11.1). Partial remission was achieved in 4 (26.7 %) patients, and disease stabilization was observed in 5 (33.3 %) patients. A favourable response was achieved in 3 (20.0 %) patients. Treatment was well tolerated; however, 11 (73.3 %) patients experienced grade 3/4 neutropenia, 10 (66.7 %) experienced thrombocytopenia, 5 (33.3 %) anaemia and 2 (13.3 %) febrile neutropenia. ConclusionsThis study failed to achieve its primary endpoint, and our data suggest limited efficacy of gemcitabine, carboplatin and veliparib for multiple relapsed/refractory GCTs. ClinicalTrials.gov Identifier: NCT02860819, registered August 9, 2016.

Palbociclib combined with endocrine treatment in breast cancer patients with high relapse risk after neoadjuvant chemotherapy: Subgroup analyses of premenopausal patients in PENELOPE-B.

518 Background: PENELOPE-B assessed efficacy of the CDK4/6 inhibitor 1-year palbociclib versus placebo added to endocrine therapy (ET) as post-neoadjuvant treatment in a high-risk breast cancer population. Palbociclib did not improve invasive disease-free survival (iDFS) compared to placebo (3-year iDFS 81.3% vs 77.7%) (Loibl et al. J Clin Oncol 2021). Here we report results from the subpopulation of premenopausal women. Methods: Patients with hormone receptor positive, HER2-negative breast cancer without pathological complete response after taxane‐containing neoadjuvant chemotherapy and at high risk of relapse (CPS‐EG score ≥3 or 2 and ypN+) were randomized (1:1) to receive 13 cycles of palbociclib 125mg daily or placebo on days 1-21 in a 28d cycle in addition to standard endocrine treatment including tamoxifen (TAM) +/- gonadotropin-releasing hormone analogue (GnRH) and aromatase inhibitor (AI) +/- GnRH. Randomization was stratified by nodal status at surgery, age ( &lt; 50 vs ≥50 years), Ki-67, region, and CPS-EG score. Results: 616/1250 patients were premenopausal at the time of enrollment, 185 of these patients (30.0%) were younger than 40 years of age. 95.2% had ypN+ after surgery; 42.8% had ypT2 and 46.8% a CPS-EG score of 3. 23.1% of the premenopausal women had a Ki67 of &gt; 15% in residual disease. 66.1% started with TAM alone; 19.3% with TAM and ovarian function suppression (OFS); and 13.6% received an AI+OFS. There was no difference in iDFS between palbociclib and placebo in the premenopausal women HR 0.948 (0.693-1.30). The 3-year iDFS was 80.6% and 78.3%, respectively. Palbociclib vs placebo in subgroups by endocrine treatment: TAM alone HR 1.05 (0.715-1.53) p = 0.817; TAM+GnRH HR 0.52 (0.267-1.02) p = 0.057 and AI+GnRH HR 1.58 (0.548-4.56) p = 0.397; pinteraction0.124. Hematologic toxicity was significantly more common with palbociclib. Non-hematological toxicity any grade palbociclib vs placebo were: fatigue 67.4% vs 51.3%; hot flushes 52.2% vs 54.8%; bone pain 15.6% vs 16.6%; and vaginal dryness 11.0% vs 11.5%. When receiving palbociclib fewer patients in the AI+GnRH group vs the TAM +/- GnRH cohort experienced anemia (54.1% vs 80.5%) and thrombocytopenia (37.8% vs 65.1%). Fatigue (75.7% vs 66.3%) and nausea (40.5% vs 24.9%) were more common with AI+GnRH than TAM +/-GnRH when palbociclib was added. Thromboembolic events were low with overall 9 events (4 vs 5; AI+GnRH 2.4% vs 1.3% TAM+/-GnRH). Conclusions: The addition of palbociclib to endocrine therapy did not improve iDFS in premenopausal women. These are the first safety results from a phase III study for the combination tamoxifen +/-GnRH and palbociclib. The addition of palbociclib to tamoxifen +/-GnRH in premenopausal women did not increase side effects compared to AI+GnRH and seems to be an alternative to AI+GnRH. Clinical trial information: NCT01864746.

Chemotherapy for biliary tract cancer: real-world experience in a single institute.

ABSTRACTThe standard chemotherapy regimen for unresectable or recurrent biliary tract cancer is gemcitabine combined with cisplatin (GC). To evaluate the effectiveness and safety of chemotherapy in patients with unresectable or recurrent biliary tract cancer in the real world, we retrospectively analyzed the clinical courses of patients who underwent chemotherapy with GC from January 2015 to November 2019. Forty-eight patients underwent the GC regimen. One patient (2.1%) achieved a complete response, seven patients (14.6%) achieved a partial response, 26 patients (54.2) achieved stable disease, 11 patients (22.9%) achieved progressive disease, and 3 patients (6.3%) were not evaluable. The overall response rate was 16.7%. The median overall survival was 14.2 months (95% CI: 13.8–14.6), and the median progression-free survival was 7.7 months (95% CI: 4.2–11.2). Thirty-nine patients (81.3%) experienced grade 3 or higher severe adverse events as follows: 54.2% experienced neutropenia, 20.8% experienced anemia, 12.5% experienced thrombocytopenia and 20.8% experienced biliary tract infection. As a second-line chemotherapy, S-1 was used in seventeen patients, and stable disease was achieved in three patients (17.6%). The GC regimen for biliary tract cancer is effective and safe for unresectable or recurrent biliary tract cancer in routine clinical practice.

Impact of Immunosuppressive Strategies on Post–Kidney Transplantation Thrombocytopenia

BackgroundThrombocytopenia after kidney transplantation is a common complication, partly induced by immunosuppressive therapies. Peritransplant thrombocytopenia may cause serious hemorrhages. We assessed the incidence of early posttransplantation thrombocytopenia (defined as a platelet count of <150,000 mm3 or <150 G/L) in de novo kidney transplant recipients (KTRs) across 4 immunosuppressive regimens. MethodsThis was a single-center observational study that included all consecutive KTRs who received either Thymoglobulin (THY) or Grafalon (GRA) and maintenance therapy of either mycophenolate-mofetil (MMF) or everolimus (EVR), associated with tacrolimus/corticosteroids. ResultsBetween July 27, 2016, and September 7, 2018, 237 KTRs were included; 64.6% experienced thrombocytopenia within the first week. Thrombocytopenia was significantly more frequent (P = .004) among GRA-treated patients (73.4%) compared to THY-treated patients (61.3%). These patients also had lower nadir platelet count (120 ± 52 vs 142 ± 48 G/L; P = .002) and lower platelet count at discharge (227 ± 94 vs 243 ± 92 G/L; P = .25). More of the GRA-EVR group had thrombocytopenia (81.0% vs 61.4% in THY-MMF, 60.9% in THY-EVR, and 69.8% in GRA-MMF; P = .081) and a worse nadir platelet count (109 ± 41 in GRA-EVR vs 141 ± 47G/L in THY-MMF, 145 ± 52 G/L in THY-EVR, and 125 ± 56 G/L in GRA-MMF; P = .011) but GRA was the only risk factor for thrombocytopenia in multivariate analyses (P = .002). Rates of hemorrhage, red blood cell transfusions, reoperations needed within the first week, delayed graft function, acute rejection, graft loss, and death did not differ between the groups after a mean follow-up of 25 ± 8 months. ConclusionsGRA associated with EVR led to more frequent and severe thrombocytopenia, although we found no significant clinical consequences.

Iguratimod treatment reduces disease activity in early primary Sjögren's syndrome: An open-label pilot study

Objectives To evaluate the efficacy and safety of iguratimod in patients with early primary Sjögren's syndrome (pSS). Methods Twenty-seven disease-modifying antirheumatic drug-naive female patients met the revised American-European Consensus Group criteria for pSS were enrolled in this open-label pilot study. Patients were treated with iguratimod 25 mg twice a day for 24 weeks. The disease activity was assessed with European League Against Rheumatism (EULAR) Sjögren's Syndrome Disease Activity Index (ESSDAI) and EULAR Sjögren's Syndrome Patient Reported Index (ESSPRI) at 12 and 24 weeks. Salivary and lacrimal gland function, laboratory, and subjective variables were also assessed. Generalized estimating equations were used to analyze parameters over time. Results ESSDAI (median, 5 versus 2 versus 2, p < .01), IgG (median, 26.6 versus 22.4 versus 21.4 g/L, p < .01) and rheumatoid factor (median, 119.9 versus 94.1 versus 83.8 lU/mL, p < .01) levels decreased significantly during iguratimod treatment. ESSPRI, salivary and lacrimal gland function, fatigue and health-related quality of life did not change during treatment. One patient experienced thrombocytopenia, and no other serious adverse effects were observed. Conclusion In this study, iguratimod treatment is safe and effective for improving disease activity and laboratory parameters in early pSS patients.

SIDE EFFECTS ASSOCIATED WITH CHEMOTHERAPY OF ACUTE LYMPHOCYTIC LEUKEMIA WITH VINCRISTINE AND ANTHRACYCLINES

Background: Acute lymphocytic leukemia or acute lymphoblastic leukemia is a malignant (clonal) disease of the bone marrow in which early lymphoid precursors proliferate and replace the normal hematopoietic cells of the marrow. It is characterized by the overproduction of immature white blood cells, called lymphoblast or leukemic blasts. Chemotherapy of cancer has many side effects. Use of vincristine and anthracyclines can lead to many side effects. It may limit the efficacy of work in daily life activities of the patient. Aim: The aim of this study is to evaluate the side effects associated with the use of vincristine and anthracyclines. Methodology: This study was conducted with the objective to assess and evaluate the side effects of vincristine and anthracyclines in MNJ Institute of Oncology and Regional Cancer Centre (RCC), Lakdikapul, Hyderabad. This study is observational in nature and the subjects enrolled under this study were about 64. Informed consent was obtained from all the subjects. Subjects recruited in this study were admitted as in patients in the hospital to receive chemotherapy. The assessment of quality of life is done by using EORTC QLQ- C30 questionnaire. Results: In this study, a total of 64 subjects with cancer were evaluated. Of 64 patients included, about 51.565 belong to age group of 0-14 years, followed by 18% in age group 15-24 years. Indicating the higher incidence of ALL in children’s specifically and the family history of non- specific cancer was found in 3 patients in the study. During the study most common side effects observed were nausea (24), vomiting (22), and shortness of breath (37) and chest pain (30) which ranges from mild to moderate in severity. Conclusion: Among 64 subjects undergoing CT for ALL, out of them ALL was dominantly diagnosed in males (89%). Of 64 patients studied, 57 patients experienced leukocytopenia, 38 experienced neutropenia, 46 experienced thrombocytopenia and anemia in 44 patients. Thus, increased rate of transfusions (45 in males, 5 in females) attributed to decreased quality of life of patients.1 male and 1 female died during the study, due to SOB due to bilirubinemia and non-adherence to the CT.

Bone marrow transplant-associated thrombotic microangiopathy without peripheral blood schistocytes: a case report and review of the literature

BackgroundBone marrow transplant-associated thrombotic microangiopathy (TA-TMA) is a relatively frequent but under-recognized and under-treated hematopoietic stem cell transplant (HSCT) complication that leads to significant post-transplant morbidity and mortality. Classic TMA-defining laboratory abnormalities appear at different times in the course of TA-TMA development, with schistocytes often appearing later in the disease course. In some severe TMA cases, schistocytes may be absent due to increased endothelial permeability. Unfortunately, many clinicians continue to perceive the presence of schistocytes as an absolute requirement for TA-TMA diagnosis, which leads to delayed recognition and treatment of this potentially fatal transplant complication.MethodsPatient chart review and PubMed literature search using the term, “transplant-associated thrombotic microangiopathy”.Case presentationA 54-year-old male IgG kappa multiple myeloma underwent a reduced intensity allogeneic HSCT from a 9/10 HLA-matched unrelated donor after conditioning with fludarabine and melphalan. On day + 27, the patient developed acute kidney injury followed by repeated episodes of diarrhea and gastrointestinal bleeding attributed to graft versus host disease (GVHD) and cytomegalovirus (CMV) colitis. Repeated colonic biopsies suggested CMV infection and GVHD. Despite appropriate treatment with antiviral therapy and immunosuppressants, the patient’s condition continued to deteriorate. He experienced concomitant anemia and thrombocytopenia as well as elevated lactate dehydrogenase and low haptoglobin levels, but a TA-TMA diagnosis was not made due to an absence of schistocytes on peripheral smear. The patient expired secondary to uncontrolled gastrointestinal bleeding. A post-mortem analysis of the resection specimen revealed extensive TMA involving numerous arteries and arterioles in the ileal and colonic submucosa as well as in the muscularis propria and deep lamina propria of the mucosa.ConclusionsTA-TMA can occur in the absence of peripheral blood schistocytes. Our experience underscores the importance of considering the diagnosis of intestinal TA-TMA in patients with refractory post-transplant diarrhea and GI bleeding, even if all classic features are not present.

Thrombocytopenia in patients with melanoma receiving immune checkpoint inhibitor therapy

BackgroundImmune checkpoint inhibitors, including antibodies against programmed death 1 (PD-1) and cytotoxic T-lymphocyte antigen 4 (CTLA-4), are being used with increasing frequency for the treatment of cancer. Immune-related adverse events (irAEs) including colitis, dermatitis, and pneumonitis are well described, but less frequent events are now emerging with larger numbers of patients treated. Herein we describe the incidence and spectrum of thrombocytopenia following immune checkpoint inhibitor therapy and two severe cases of idiopathic thrombocytopenic purpura (ITP).Case presentationsA 47-year-old female with recurrent BRAF mutant positive melanoma received combination anti-PD-1 and anti-CTLA-4. Two weeks later, she presented with mucosal bleeding, petechiae, and thrombocytopenia and was treated with standard therapy for ITP with steroids and intravenous immunoglobulin (IVIG). Her diagnosis was confirmed with bone marrow biopsy, and given the lack of treatment response, she was treated with rituximab. She began to have recovery and stabilization of her platelet count that ultimately allowed her to be retreated with PD-1 inhibition with no further thrombocytopenia. A second patient, a 45-year-old female with a BRAF wild-type melanoma, received anti-PD-1 monotherapy and became thrombocytopenic 43 days later. Three weeks of steroid treatment improved her platelet count, but thrombocytopenia recurred and required additional steroids. She later received anti-CTLA-4 monotherapy and developed severe ITP with intracranial hemorrhage. Her ITP resolved after treatment of prednisone, IVIG, and rituximab and discontinuation of checkpoint inhibition. In a retrospective chart review of 2360 patients with melanoma treated with checkpoint inhibitor therapy, <1% experienced thrombocytopenia following immune checkpoint inhibition, and of these, most had spontaneous resolution and did not require treatment.ConclusionsThrombocytopenia, especially ITP, induced by immune checkpoint inhibitors appears to be an uncommon irAE that is manageable with observation in mild cases and/or standard ITP treatment algorithms. In our series, the majority of patients had mild thrombocytopenia that resolved spontaneously or responded to standard corticosteroid regimens. However, in two severe cases, IVIG and rituximab, in addition to steroids, were required. Checkpoint inhibition was resumed successfully in the first patient but rechallenge was not tolerated by the second patient.